The purpose of this research program is to develop safe and effective treatments for hereditary neurological disorders. Specific research accomplishments in the past year include the following: validation of the Adult Myopathy Assessment Tool (AMAT) in patients with spinal and bulbar muscular atrophy (SBMA), completion of a randomized, controlled trial of exercise in SBMA, initiation of a clinical trial of BVS857 in SBMA, and continuation of a protocol for evaluation of skeletal and cardiac imaging with a trial of oligonucleotide therapy in Duchenne muscular dystrophy (DMD): (1) The AMAT is a performance-based battery comprised of functional and endurance subscales that can be completed in approximately 30 minutes without the use of specialized equipment. The purpose of this study was to determine the construct validity and internal consistency of the AMAT with a sample of adults with SBMA. AMAT validity was assessed in 56-male participants with genetically confirmed SBMA (mean age, 53&#8201;&#8201;10 years). The participants completed the AMAT and assessments for disease status, strength, and functional status. Lower AMAT scores were associated with longer disease duration (r = -0.29; P < 0.03) and lower serum androgen levels (r = 0.49-0.59; P < 0.001). The AMAT was significantly correlated with strength and functional status (r = 0.82-0.88; P < 0.001). The domains of the AMAT exhibited good internal consistency (Cronbach's &#945; &#8201;=&#8201;0.77-0.89; P < 0.001). The AMAT is a standardized, performance-based tool that may be used to assess functional limitations and muscle endurance. The AMAT has good internal consistency, and the construct validity of the AMAT is supported by its significant associations with hormonal, strength, and functional characteristics of adults with SBMA. This trial is registered with Clinicaltrials.gov identifier NCT00303446. (2) We recently finished a study to examine the safety and efficacy of exercise in SBMA patients. We enrolled 50 men with genetically confirmed SBMA. This was a randomized, evaluator blinded, trial with 25 subjects in each exercise arm. Following informed consent, the subjects underwent initial medical and physical evaluations followed by a series of neurological tests and blood work over a two-day outpatient visit at the NIH. The subjects provided blood for analysis of hormonal levels and assessment of any potential muscle damage. On the second day of their visit, the subjects were randomized and taught a series of either functional or stretching exercises that they engage in as part of the study and control arms, respectively. Following the baseline visit to NIH, the subjects were monitored throughout the study with telephone contacts and other measures including video recording to monitor their progress and compliance. The subjects returned to the NIH at the end of a 12 week period at which time the physical and laboratory testing was repeated. The primary outcome measure used was the Adult Myopathy Assessment Tool . Secondary outcome measures were QMA, the Timed Up and Go test, a quality of life measure (SF-36v2), adverse event questionnaires, a Computerized Dynamic Posturography assessment of balance, accelerometer measurements of exercise effort, and progressive height sit-to-stand testing. Several exploratory biomarkers that may be affected by exercise were evaluated, including insulin-like growth factor-1 (IGF-1), IGF binding protein 3, testosterone, growth hormone, and creatine kinase. Beck Depression Inventory testing was also used to determine if the subjects mood is affected by exercise. The results of the study are now being analyzed and prepared for publication. (3) Preclinical studies of SBMA have shown mitigation of disease manifestations with IGF-1. We have started a study to evaluate the safety, tolerability, and preliminary efficacy in SBMA patients of BVS857, a drug that targets the IGF-1 pathway. The participants are ambulatory, genetically confirmed SBMA patients with symptomatic muscle weakness who have serum IGF-1 levels of 170 ng/ml or less. Up to 30 patients will be screened at the NIH for enrollment. This is a double-blind, placebo-controlled study in two parts. The purpose of Part A is to confirm the safety and tolerability of selected doses of BVS857 in patients with SBMA, and to investigate its pharmacokinetic and pharmacodynamic effects in SBMA patients. Following successful demonstration of safety and tolerability of BVS857 in SBMA patients in Part A, BVS857 will be given weekly for 12 weeks in Part B. The primary outcome measures are safety and tolerability of BVS857 in patients with SBMA, and effects of BVS857 on thigh muscle volume in SBMA patients after 12 weeks of dosing. Secondary and exploratory outcome measures include the following: effect of BVS857 on extremity muscle function by the AMAT, effects of BVS857 on other measures of muscle strength and function, measures of BVS857, and pharmacodynamic biomarkers of BVS857 effect in blood and muscle samples. (4) DMD is the most frequent inherited fatal childhood disease. Antisense oligonucleotide-induced exon skipping is a promising therapeutic strategy for DMD that is currently being explored in clinical trials. Magnetic resonance imaging (MRI) and ultrasound imaging methods are sensitive to key processes in dystrophic muscle such as edema and fat infiltration and therefore could serve as a biomarker of disease progression and therapeutic response. We recently completed a study protocol to explore the potential of these imaging biomarkers for assessing the effects of the oligonucleotide GSK2402968 in ambulatory boys with DMD, and the results are now being analyzed. The primary objective was to assess longitudinal changes in skeletal muscle structural MRI measures reflecting fat and edema in the lower extremities in ambulatory boys with DMD receiving GSK2402968 or placebo. We enrolled 9 ambulatory boys with DMD. 20 healthy volunteer/control boys matched for the age-range were recruited to obtain comparative data for the imaging studies. This prospective study of skeletal muscle, cardiac, and diaphragm imaging at the NIH was offered to subjects participating in a phase 2, double blind, exploratory parallel-group, placebo-controlled clinical study in ambulatory subjects with DMD resulting from a mutation that can be corrected by exon 51 skipping induced by GSK2402968. Subjects traveled with a family member to the NIH for MRI and ultrasound assessments during the screening phase of the parent study and additionally, if randomized, then at the following time points in the parent study: at 12 weeks, and 24 weeks during the blinded treatment period; and finally, after completion of 24 weekpost-treatment phase (at 48 weeks). If not randomized, the subjects had a one-time evaluation during the screening phase of the parent study. Data was also obtained from healthy boys for comparisons to allow exploration of MRI and ultrasound measures specific to pathology in the ambulatory boys with DMD. The primary outcome measure for the study was MRI-detected change in skeletal muscle fat in the lower extremities from baseline in boys with DMD receiving GSK2402968 or placebo. Secondary outcome measures included changes in the following outcome measures at 12, 24, and 48 weeks from baseline in boys with DMD receiving GSK2402968 or placebo: relative muscle fat/water assessed by skeletal muscle MRI T1 imaging, muscle edema assessed by T2 imaging, and cardiac function and myocardial fat and edema as measured by cardiac MRI. Exploratory outcome measures included changes in muscle water diffusivity as assessed by diffusion MRI; the effects of exercise on selected MRI measures in leg muscles, muscle ultrasound to monitor changes in skeletal muscle volume, echogenicity, and stiffness; and MRI assessment of diaphragm motion.